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- Adams, D., et al.
(författare)
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Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis
- 2018
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 379:1, s. 11-21
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin.METHODS: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters] x albumin level in grams per liter; lower values indicated worse nutritional status).RESULTS: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (+/- SD) mNIS+7 at baseline was 80.9 +/- 41.5 in the patisiran group and 74.6 +/- 37.0 in the placebo group; the least-squares mean (+/- SE) change from baseline was -6.0 +/- 1.7 versus 28.0 +/- 2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (+/- SD) baseline Norfolk QOL-DN score was 59.6 +/- 28.2 in the patisiran group and 55.5 +/- 24.3 in the placebo group; the least-squares mean (+/- SE) change from baseline was -6.7 +/- 1.8 versus 14.4 +/- 2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08 +/- 0.02 m per second with patisiran versus -0.24 +/- 0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7 +/- 9.6 versus -119.4 +/- 14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups.CONCLUSIONS: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis.
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| 3. |
- Berk, JL, et al.
(författare)
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The diflunisal trial : update on study drug tolerance and disease progression
- 2011
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Ingår i: Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis. - : Informa UK Limited. - 1744-2818. ; 18:Suppl. 1, s. 191-192
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: Familial amyloidotic polyneuropathy (FAP) is a lethal genetic disorder that affects the peripheral and autonomic nervous systems, heart, gastro-intestinal (GI) tract, and soft tissues. Disease progression is increasingly reported following liver transplantation, the only proven treatment for FAP. Small molecule thyroxine mimetics stabilize transthyretin, inhibiting FAP amyloid fibril formation under stringent in vitro conditions. We report on the progress of an international, randomized placebo-controlled study designed to determine the effect of diflunisal, a thyroxine mimetic, on neurologic disease progression in patients with active FAP. Our experience to date indicates diflunisal is well tolerated by this study cohort and that neurologic disease advances more rapidly in FAP than it does in diabetes mellitus. Background: Transthyretin-related familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant genetic disorder that predominantly affects the peripheral nervous system. FAP amyloid fibrils result from the misfolding of transthyretin, a transport protein predominantly produced by the liver. Although liver transplantation effectively treats patients with certain FAP mutations and limited disease, reports increasingly document progressive amyloid deposition following transplantation [1,2]. Alternative treatments are needed. In vitro investigations and a phase I clinical trial have demonstrated that thyroxine and small molecule mimetics, e.g. diflunisal, inhibit tetrameric transthyretin dissociation and suppress amyloid fibril formation [3,4]. Methods: To examine the effect of diflunisal on disease progression in FAP, we designed a randomized, placebo controlled, double blind, multicenter international study employing the validated diabetic (DM) polyneuropathy metric, Neurologic Impairment Score + 7 attributes (NIS+7®), as the primary endpoint. A two-point change in NIS+7 correlates with clinically detectable progression of peripheral neuropathy among diabetics [5]. Entry criteria include proven FAP genotype, biopsy-proven amyloid deposits, and peripheral or autonomic neuropathy. Patients with alternate causes of neuropathy, other NSAID use, severe heart or kidney dysfunction, or previous liver transplantion are excluded. Study evaluations occur at entry, 6, 12, and 24 months. Adverse are collected by monthly telephone interviews, diary entries, and study site visit interactions. Relatedness of adverse events to study drug is assigned according to documentation in the investigational brochure, the protocol, the informed consent form; or at the investigator's discretion. Results: To date, 90 subjects have enrolled – 62 men and 28 women with median age 63 years (range 27–76 years). Adverse events tabulated by affected organ systems predominantly involved gastrointestinal events, more often attributed to disease complications than study drug side effects (Table 1). Although rare events, congestive heart failure in two subjects and GI bleeding in another prompted study drug discontinuation. Two disease-related deaths have occurred, both off study drug. Aggregate data from all study subjects (placebo and active drug arms) followed for at least 12 months identified a 3.2 point increase in median NIS+7 summated scores. In contrast, Dyck et al. [6] reported an annual 0.85 point increase in NIS+7 median scores in a large cohort of diabetics with polyneuropathy. Taken together, NIS+7 detected neurologic disease progression in this FAP cohort after 12 months observation. Additionally, NIS+7 measured disease advanced 3.5 times faster in our aggregate FAP study population than previously reported in DM. Conclusions: Diflunisal is well tolerated in FAP patients participating in the study. NIS+7, a composite scoring system, appears to be an effective study instrument for ATTR neuropathy, detecting significant change over 12 months observation. Neurologic disease progresses more rapidly in FAP than DM cohorts. The exact rate of disease progression in untreated FAP subjects detected by NIS+7 awaits unblinding of the data. These data will provide basis for future study design in FAP patients.
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| 5. |
- Hammarström, Per, et al.
(författare)
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D18G transthyretin is monomeric, aggregation prone, and not detectable in plasma and cerebrospinal fluid : A prescription for central nervous system amyloidosis?
- 2003
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 42:22, s. 6656-6663
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Tidskriftsartikel (refereegranskat)abstract
- Over 70 transthyretin (TTR) mutations facilitate amyloidosis in tissues other than the central nervous system (CNS). In contrast, the D18G TTR mutation in individuals of Hungarian descent leads to CNS amyloidosis. D18G forms inclusion bodies in Escherichia coli, unlike the other disease-associated TTR variants overexpressed to date. Denaturation and reconstitution of D18G from inclusion bodies afford a folded monomer that is destabilized by 3.1 kcal/mol relative to an engineered monomeric version of WT TTR. Since TTR tetramer dissociation is typically rate limiting for amyloid formation, the monomeric nature of D18G renders its amyloid formation rate 1000-fold faster than WT. It is perplexing that D18G does not lead to severe early onset systemic amyloidosis, given that it is the most destabilized TTR variant characterized to date, more so than variants exhibiting onset in the second decade. Instead, CNS impairment is observed in the fifth decade as the sole pathological manifestation, however, benign systemic deposition is also observed. Analysis of heterozygote D18G patient's serum and cerebrospinal fluid (CSF) detects only WT TTR, indicating that D18G is either rapidly degraded postsecretion or degraded within the cell prior to secretion, consistent with its inability to form hybrid tetramers with WT TTR. The nondetectable levels of D18G TTR in human plasma explain the absence of an early onset systemic disease. CNS disease may result owing to the sensitivity of the CNS to lower levels of D18G aggregate. Alternatively, or in addition, we speculate that a fraction of D18G made by the choroid plexus can be transiently tetramerized by the locally high thyroxine (T4) concentration, chaperoning it out into the CSF where it undergoes dissociation and amyloidogenesis due to the low T4 CSF concentration. Selected small molecule tetramer stabilizers can transform D18G from a monomeric aggregation-prone state to a nonamyloidogenic tetramer, which may prove to be a useful therapeutic strategy against TTR-associated CNS amyloidosis.
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| 6. |
- Sekijima, Y., et al.
(författare)
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The biological and chemical basis for tissue-selective amyloid disease
- 2005
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 121:1, s. 73-85
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Tidskriftsartikel (refereegranskat)abstract
- Factors controlling the onset and progression of extracellular amyloid diseases remain largely unknown. Central to disease etiology is the efficiency of the endoplasmic reticulum (ER) machinery that targets destabilized mutant proteins for degradation and the enhanced tendency of these variants to aggregate if secreted. We demonstrate that mammalian cells secrete numerous transthyretin (TTR) disease-associated variants with wild-type efficiency in spite of compromised folding energetics. Only the most highly destabilized TTR variants are subjected to ER-associated degradation (ERAD) and then only in certain tissues, providing insight into tissue selective amyloidosis. Rather than a "quality control" standard based on wild-type stability, we find that ER-assisted folding (ERAF), based on global protein energetics, determines the extent of export. We propose that ERAF (influenced by the energetics of the protein fold, chaperone enzyme distributions, and metabolite chaperones) in competition with ERAD defines the unique secretory aptitude of each tissue. Copyright ©2005 by Elsevier Inc.
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